The purpose of this FOA is to solicit applications for the
Nuclear Receptor Signaling Atlas Hub (NURSA). The overriding goal of NURSA
will be to significantly advance basic science findings to applications for
human diseases and conditions for which nuclear receptors (NRs) play an
integral role. The organization of NURSA will consist of a Hub that is
collaborative in nature by providing the integration and cohesion needed to
aggregate, annotate, and present in a user friendly fashion state-of-the-art
data from a series of collaborative research projects. The Hub will support a
public web portal (www.nursa.org) as part
of a comprehensive approach to elucidating the role of NRs in normal
physiology and disease. NURSA will assist in generating important new
concepts and validated datasets that will provide the foundation for research
leading to a more comprehensive understanding of the role of NRs in human
physiology and metabolic disease. The NURSA Hub will integrate the work of
investigators who will be funded through a series of NURSA Data Source
Projects (NDSP). NDSPs will supply a steady stream of novel and cutting edge
data derived from projects that will explore newly emerging opportunities in
the NR field relevant to the missions of NIDDK and NICHD, and/or address key
technological or conceptual roadblocks to progress. The Hub will foster
annotation, and conversion to formats readily accessible by the broader
community through the public web portal.

Key Dates

Posted Date

October 21, 2011

Letter of Intent Due Date

February 8, 2012

Application Due Date(s)

March 7, 2012

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

June/July, 2012

Advisory Council Review

October, 2012

Earliest Start Date(s)

December, 2012

Expiration Date

March 8, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the PHS398
Application Guide except where instructed to do otherwise (in this FOA or
in a Notice from the NIH Guide
for Grants and Contracts). Conformance to all requirements (both in
the Application Guide and the FOA) is required and strictly enforced. While
some links are provided, applicants must read and follow all application
instructions in the Application Guide as well as any program-specific
instructions noted in Section IV. When
the program-specific instructions deviate from those in the Application Guide,
follow the program-specific instructions. Applications that do not
comply with these instructions may be delayed or not accepted for review.

The
Nuclear Receptor Signaling Atlas (NURSA) is comprised of a collaborative and
integrated network of investigators designed to advance our understanding of
the role of Nuclear Receptors (NR) in health and disease. Moving forward NURSA
will now center around a Hub consisting of an informatics resource and a
community web portal to support a scientific agenda. Although NURSA has built a
considerable amount of cohesion leading to significant advances, it is
imperative that NURSA reach out to the broader community. Accordingly, the Hub
will integrate the work of independent and experienced investigators through a
series of peer reviewed NURSA Data Source Projects (NDSP). Together the Hub and
NDSP investigators will constitute a consortium (NURSA). The Hub will provide
the capability for data aggregation, annotation, and delivery in user friendly
format for the wider community through a public web portal (www.nursa.org). The NDSPs, and other
affiliated projects, will serve as the development and research arm of NURSA,
acting as the source groups for new and unique concepts and data. The Hub will
seek to standardize descriptors across these groups, aggregating and annotating
the data for public availability through the web portal. The Hub will provide the
administrative support to facilitate the collaborative nature of NURSA. The Hub
will: 1) develop and manage the informatics resource and a web portal (www.nursa.org),
2) serve as the focal point for a program of research through a series of NURSA
Data Source Projects (NDSP), 3) facilitate outreach by extending NURSA to the
broader research community including assuring a steady flow of new data to the
web portal from other investigators working on NRs, 4) work with NIH Staff
through the cooperative agreement mechanism to establish effective governance,
including integration of NDSPs, 5) manage, integrate and communicate data to
the community, and finally, 6) organize and implement regular steering
committee meetings and investigators’ retreats.

NURSA was initially funded by NIDDK, the NCI and the NIA (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-01-026 with the goal to accrue, develop and communicate information about the Orphan
Nuclear Receptor subfamily of Nuclear Hormone Receptors. Subsequent expansion included
all NRs as well as relevant coregulators, ligands, and downstream targets.
NURSA was re-competed in 2006 (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-06-503.html)
with co-sponsorship by NHLBI and NIEHS. NURSA has brought a collaborative
approach to the generation of new research tools, reagents, technologies and
concepts vital for developing an integrated understanding of the molecular
regulation of nuclear receptors and associated coregulators as they impact human
health and disease. Among its accomplishments, NURSA has established
comprehensive atlases of NR and coregulator expression in mouse and human
tissues and cells (www.nursa.org). NURSA
has also developed an integrated multi-'omics discovery and hypothesis-testing/-validating
platform that included often high throughput expression profiling and
semi-quantitative proteomics and metabolomics analyses that ultimately
developed a comprehensive base of knowledge of NR structure, function, and role
in disease. Large datasets have been made publicly available through the web portal,
in turn facilitating integration of data from many sources through the online
molecule pages. NURSA has accelerated discovery in the areas of metabolism,
cancer, aging, cardiovascular disease, response to the environment, and
reproductive diseases and disorders. NURSA activities have allowed a more
comprehensive understanding of the potential role for NRs in disease mechanisms
and as targets for the development of novel approaches to therapeutics. NURSA
now seeks to focus on translating the developed and accrued knowledge into
deeper understanding of the roles played by NRs in human disease, including new
and novel approaches to treatment.

Research Objectives

The overriding goal of NURSA will be to significantly
advance translation of basic science findings to applications for human
diseases and conditions for which NRs play an integral role. A multifaceted,
interdisciplinary, coordinated and collaborative approach on several fronts
will be required to generate the key reagents, assays, strategies and
proof-of-concept studies required for the development of a more complete
understanding of the role of NRs in physiology and pathophysiology of common
and chronic diseases including diabetes, obesity, metabolic dysregulation, CVD,
cancer, response to the environment, processes of aging, and reproductive
diseases and disorders. The basic NURSA platform has employed a high
throughput integrated ‘omics approach (genomics, proteomics, bioinformatics,
metabolomics) to discovery of NR and coregulator expression in specific tissues
and cells, together with an understanding of the role of ligands as they impact
target genes and gene networks. This has fostered a systems biology
understanding of the underlying physiology and role in disease. NURSA now seeks
to exploit this platform to catalyze movement toward a tissue and disease
oriented understanding of the role(s) of NRs and coregulators in human disease.

The NURSA Hub will provide support for discovery and
hypothesis-generating/testing research through two components: 1) an Informatics
Resource/web portal, and 2) an integrated series of NURSA Data Source Projects
(NDSP). The Hub will be publically available and open to collaborative
interactions through the web portal (www.nursa.org)
and the NDSPs will be openly competed and peer reviewed. The NSDPs will be
integrated with the Hub to form the NURSA Consortium. NDSP investigators will
utilize the Hub resources for informatics support and will contribute to a
constant flow of new data that will be integrated with the NURSA molecule
pages. This new information will be made freely available through the community
web portal. The Hub will provide the central support function of NURSA
including data accrual, formatting and mining of the data, as well as
administrative support and outreach. The collaborative NDSPs will carry out
the necessary studies to generate/translate new and accrued data into advances
in understanding human health and disease. The use of the cooperative agreement
mechanism will guarantee the integrated and collaborative nature of the
consortium in partnership with the NIH. The individual nature of the NDSPs
through the cooperative agreement mechanism will lead to a NURSA team comprised
of leaders in the field with equal stakes in the outcomes. The role of the Hub
will be to perform many vitally important functions that contribute to the
functional integrity and cohesive infrastructure of the consortium. The Hub
will facilitate sharing of information with other consortia, databases, and
scientific journals, as needed. By providing basic administrative support for
the consortium, the Hub will also facilitate management of the NURSA Consortium
through a Steering Committee, interactions with an External Evaluation
Committee, interactions with NIH Project Scientist(s) and Program Director(s),
and outreach programs to the broader research community.

The Informatics Resource will be the support arm of the Hub,
including data aggregation (from the NSDPs and other affiliated sources) and
integration of projects brought forward through the NDSP and other outreach
efforts. The Hub will provide the administrative structure to allow for integration
of both components into an interactive consortium. A major outreach role for
the Hub will be to work with the broader community as they and the NIH
identifies cutting edge ideas to develop solutions leading to new advances. The
NDSPs will ensure a source for discovery and data flow into the Hub. For
example, data accrued at the Hub may provide the basis for a crucial question
to be addressed by an NDSP project. Furthermore, data resulting from an NDSP
could be assimilated directly into the Hub molecule pages for rapid
dissemination. The Hub will work with the collaborating labs to format the
data for subsequent integration with other such data and with the NURSA
molecule pages. The resulting data will be publicly available and searchable
through the web portal. Understanding that there are many other sources of data
that can be aggregated with the NURSA collection, the Hub will need to leverage
existing public datasets to further enrich the information available through
NURSA. The Informatics arm of the Hub will provide opportunities for
collaborations with investigators independently funded by other means from
which additional data can be sourced. To accomplish this goal the Hub will
develop an outreach plan for accruing and aggregating data from individual
investigators drawn from outside the consortium as well as relevant scientific
journals. These goals will be achieved through outreach to potential users and
stakeholders and could include collaborators drawn from research (e.g. R-, or
P-series) grants not initially a part of NURSA. Such projects may subsequently
develop collaborative alliances with NURSA.

The Hub will replace the current NURSA structure but will continue
to provide support for a consortium not only by maintaining the NURSA molecule
pages, databases, and datasets, and the public portal (http://www.nursa.org/), but also the online
public e-journal Nuclear Receptor Signaling. Responsibilities will also include
participation in the continuing evolution and development of the evolving NIDDK
trans-consortium data network (NIDDK Consortium Interconnectivity Network; www.dkcoin.org, or its successor) that was
developed with participation by NURSA. Through the Hub NURSA will adapt,
develop and implement any software necessary for data handling and analysis,
internet connectivity, and web services associated with dkCOIN. NURSA will
support: 1) search tools for gene expression studies, 2) genome-wide profiling
of epigenetic marks, 3) imaging-based datasets, 4) ligand structural
repositories, and 5) new web interfaces that will allow data mining and
meta-analyses across multiple databases, including those already housed at
NURSA such as transcriptomine and the coregulator interactome. The Hub will
facilitate sharing of information with other consortia, databases, and
scientific journals, as well as potential outreach programs to the broader
research community. An important role will be to establish data standards,
analysis protocols, and metadata requirements for the integration of consortium
investigators derived from the individual NDSPs, as well as any other
associated projects identified through outreach efforts.

Scientific Scope

The overriding goal of NURSA at this point will be to
enhance the translation of in vitro and model organism (e.g. mouse) models of
disease to human disease. Core questions to be addressed, including for NDSPs,
that help to define the central focus may include but are not restricted to:

2. Can human iPSC’s be used to model NR actions
in and development of disease?

3. How do NRs recruit different and specific
coregulator complexes in response to different signals (e.g. environmental
cues, or ligands) to give specific and selective physiological or
pathophysiological outcomes? Does transient interactome formation in response
to a particular NR signal form a tissue or cell specific epigenome leading to a
specific physiological or pathophysiological outcome?

4. For a given NR signal, are there
characteristic metabolic outcomes that are predictive of human disease?

5. Can chemical biology tools and approaches be
used to identify new therapeutic targets with the necessary selectivity and
specificity to be pursued as novel pre-therapeutic leads for diseases where NRs
are implicated and possibly help to identify new biology?

NIDDK, through the Division of Diabetes, Endocrinology and
Metabolic Diseases, is interested in how NRs impact metabolic diseases,
including obesity, diabetes, NASH, osteoporosis, and dysregulated
carbohydrate/lipid metabolism contributing to the metabolic syndrome. Emphasis
is on translation of in vitro and model organism studies to human tissues and
diseases. Examples include how NRs contribute to pathophysiology in key
metabolic tissues, including adipose, liver, skeletal muscle, and the
macrophage-adipose or -liver dynamic. Specifically the genomic and/or temporal
and tissue-specific expression of NRs, related transcription factors,
coregulators, and chromatin remodeling factors as they impact the cellular epigenome
are key questions that can be addressed in high throughput fashion where
integration of multi-‘omic and informatics analyses can help to pinpoint
pathways central to disease development, progression, and treatment often
through discovery-based studies that can be validated through
hypothesis-generation and –testing in human tissues.

NICHD has recognized that it is now increasingly evident
that several diseases and disorders of reproduction such as polycystic ovary
syndrome (PCOS), endometriosis and leiomyoma may be due, at least in part, to
alterations in sex steroid signaling pathways necessary for normal
responsiveness of various components of the
hypothalamo-pituitary-gonadal-reproductive axis. Moreover, variants of NRs
important for sexual development such as Steroidogenic Factor-1 (SF-1, NR5A1)
may be associated not only with disorders of sex development such as primary
adrenal failure, gonadal dysgenesis and hypospadias, but with primary ovarian
insufficiency, male factor infertility and endometriosis as well. Therefore,
this FOA may provide the NICHD with an opportunity to pursue the underlying
etiologies of the aforementioned conditions as they relate to the NR
interactome with the ultimate goal of identifying novel strategies for
prevention, diagnosis and treatment of these conditions.

Functions of the Hub:

In order to carry out this scope the successful applicant
will present a strategy and plan to fulfill all responsibilities, functions and
activities required of the NURSA Hub, including:

Informatics Resource:

To maintain currency and relevancy NURSA requires an influx
of data that can be integrated with the molecule pages and serve to inform new
ideas and concepts. The NDSP projects will serve as one arm of that task. These
new projects from established investigators will serve as the research arm of
the Hub. The Hub Resource must have a state-of-the-art capacity to handle new
and emerging forms of high throughput (HT) data for NRs. The Informatics arm of
the Hub will need to establish a strong presence through expertise in analysis,
annotation, and web design. This will include adapting, developing, and
deploying the necessary tools for the aggregation, annotation, and presentation
of data such as that obtained from (e.g.) qPCR, next generation sequencing,
epigenomic, metabolomic studies, image analysis and others, as needed. The Hub
will ultimately need to develop or adapt tools for (e.g.) the analysis of
genome-wide profiling of epigenetic marks as they apply to NR signaling and function
so that comparisons can be made across different cells and tissues. The Hub
will seek to standardize approaches for data validation and presentation. Tools
to analyze such data may include cistrome and proteome pipeline analysis
suites, cytoscape, and others. The Hub will develop and provide the capability
for users to mine the data displayed, as raw or filtered data sets or as
components of the NURSA molecule pages. The aim will be to provide a valuable
service to help catalyze the formation and testing of new hypotheses about NRs
and their roles in disease. The NURSA Steering Committee will determine final
policies regarding access to these Hub resources. It is not the intention of
NURSA to have the informatics resources reserved for the exclusive use of any
one individual or project.

Management of the data will likely require database tools
including relational databases. Public access may require an expanded user-interface
to allow for various types of queries. NURSA will need to provide solutions
proposed for database schemas and user-interfaces and be flexible and adaptable
enough to build new and required features following the initial deployment. Any
proposed solution must clearly demonstrate that such flexibility exists or can
easily be added after the initial deployment.

Key functions of the NURSA webportal include access to and
sharing of databases, information about reagents and ideas between NURSA
members as well as the scientific community at large. The NURSA molecule pages
represent the results of significant annotation and curation efforts for
studies conducted by NURSA, and other, investigators. The development of search
tools for genes, their transcripts, and their profiles in expression studies,
including the transcriptomine module, have been made freely available through
the web portal. Similar efforts have resulted in accrual of information about
the coregulators that contribute to the NR interactome. Complex cellular
imaging datasets reflecting gene expression patterns or transient signaling
events are also likely to be generated. New tools and annotation protocols will
have to be expanded, developed or adapted so that information can be retrieved
and analyzed across datasets that are different by nature and accessible
through the web portal. Likewise, NURSA will have to develop appropriate search
and analysis tools that can lead to analyses between NURSA-generated data
collections and other relevant databases available through the linked sources,
as well as new interfaces that can allow the seamless sharing of data with
other NIH-sponsored consortia particularly through dkCOIN, or its successor.
NURSA has also developed and maintained a strategic alliance with The Endocrine
Society, a professional scientific society and its signature journal, Molecular
Endocrinology. These activities will continue and include reciprocal curation
of relevant published papers, and archiving of datasets. Strategic alliances
with other relevant scientific journals will be considered and implemented if
mutually beneficial. The Hub should provide a maximally efficient means for
data collection, storage, and availability, from a variety of sources, and
ensure that designs are adaptable, extensible and portable. Consideration
should be given to development within a cloud computing environment to enhance
long-term support for the data. A mix of existing and newly developed tools
should be considered, including the development, acquisition, and
implementation of any needed software, middleware, network interface, web
services, and data storage. The Hub must demonstrate flexibility in the design
principles of the user-interface as well as the underlying software infrastructure
and thereby support the simplest to the most sophisticated tasks. Most queries
will be simple, single query searches, followed up with finding the most
interesting related molecules, pathways or datasets, and including data mining
of related databases such as those presented by NCBI of the National Library of
Medicine (www.ncbi.nih.gov). These
requirements may imply that the proposed user-interface solution incorporate
plug-ins or other similar approaches. The database schema should be available
to the community and should be supported by a clearly documented API.

Facilitate interactions with other investigators, centers
and consortia as part of an outreach effort:

Outreach has been a hallmark of NURSA and has included Pilot
& Feasibility studies, Collaborative Bridging Projects, as well as
recruitment of affiliated members as part of a broader Consortium. To ensure
continued influx of new ideas, data, and investigators, NURSA will utilize a
competitive and peer reviewed mechanism to recruit NURSA Data Source Projects
(NDSP). These projects, funded for 2-5 years as subcontracts from the Hub will
address difficult issues, roadblocks, unique opportunities or emerging
questions in the NR field and solicit novel and innovative ideas for which the
NURSA mulit-'omics discovery platform may be well suited. NDSP topics will seek
to explore the cutting edge, including high risk/high gain ideas-all relevant
to NRs and the mission of NIDDK (http://www2.niddk.nih.gov/Research/ScientificAreas/default.htm)
and the interests of NICHD. Outreach to
the broader community will seek to include leading investigators in the field
willing to share expertise, data, and resources in return for affiliated
membership in a new NURSA Consortium. The web portal, including the e-journal
Nuclear Receptor Signaling, will serve as the vehicle for dissemination of
information, including datasets, and new/novel concepts. The Hub will also contribute
to collaborations between NURSA and other relevant NIDDK or NIH sponsored
projects to facilitate broader sharing of data and resources, including through
the NIDDK Consortium Interconnectivity Network (www.dkcoin.org),
or its successor. Such interactions may include both joint scientific events
and integration of research databases. A continuing outreach effort by NURSA
will also require developing a means for identifying and querying key
stakeholders and users of its content as it seeks to accrue and communicate
information and concepts to the broader research community, including other
useful publically available datasets. The Hub will be responsible for defining
and displaying online definitive policies regarding inclusion as a member of
the consortium, PI roles and responsibilities, and the NURSA data sharing
policy.

Management of the consortium:

To facilitate new discovery essential to continued progress,
the Hub will manage competitions for the NDSPs, integrating these into the
consortium. The Hub will be responsible for broadcasting availability as well
as for administrative handling of NDSPs. However, the NIH, in consultation
with a wide range of experts, will play an important role in defining the
topics to be considered in the open competitions. NDSP investigators must agree
to comply with NURSA policies regarding data sharing and availability. PD(s)/PI(s)s
for the NDSPs will be funded for 2-5 years at up to $150,000 (T/C) per year and
must provide milestones to be evaluated yearly. The NIH will identify a panel
of External Experts not associated with NURSA to assist in topic identification
and peer review. The Hub will be responsible for instituting a Scientific
Project Online Tracker (SPOT) program, such as has been used by the NIDDK Beta
Cell Biology Consortium (see BCBC; http://www.betacell.org/research/pilot/?rfa)
to assist in receipt and administration of NDSPs. The Hub will serve as the
portal through which the solicitations for NDSPs will be conducted. A timeline
should be provided for the solicitation, review, and funding of NDSPs. The Hub
will need to initiate the first competition for NDSPs coincident with onset of
NURSA funding. The Hub will also be responsible for the annual investigator
retreat and EEC meeting.

Governance and Leadership Plan

Applications to this FOA should include a plan that defines
the overall governance and organizational structure of the NURSA consortium. Included
should be plans for formation of a steering committee, to be comprised of the PD(s)/PI(s)
of the Hub, the NIH Project Scientist and the PIs of NDSPs. In addition
consideration of a projected affiliated membership, regular meetings, SC
actions, and roles in governance of the cooperative agreement should be
described. More than one PD(s)/PI(s), or multiple PD(s)/PI(s), may be
designated on the application for projects that require a team science approach
that clearly does not fit the single-PD(s)/PI(s) model. Additional information
on the implementation plans and policies and procedures to formally allow more
than one PD(s)/PI(s) on individual research projects is available at: http://era.nih.gov/ElectronicReceipt/preparing.htm for instruction).

Applications designating multiple PD(s)/PI(s) should include
a section of the research plan, entitled Multiple PD(s)/PI(s) Leadership Plan
(Section 12 of the Research Plan in the PHS 398). A rationale for choosing a
multiple PD(s)/PI(s) approach should be described. The governance and organizational
structure of the leadership team and the research project should be described,
including communication plans, process for making decisions on scientific
direction, and procedures for resolving conflicts. The roles and
administrative, technical, and scientific responsibilities for the project or
program should be delineated for the PD(s)/PI(s) and other collaborators.

If budget allocation is proposed, the distribution of
resources to specific components of the project or the individual PD(s)/PI(s)
should be delineated in the Leadership Plan. In the event of an award, the
requested allocations will be identified in the Notice of Award (NoA).

Section
II. Award Information

Funding Instrument

Cooperative Agreement

Application Types Allowed

New

The OER
Glossary and the PHS398 Application Guide provide details on these application
types.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

Applicant organizations must complete the following registrations
as described in the PHS398 Application Guide to be eligible to apply for or
receive an award. Applicants must have a valid Dun and Bradstreet Universal
Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due
date. Applicant organizations are strongly encouraged to start the registration
process at least4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

It is anticipated that the PD(s)/PI(s) have requisite
experience in the devleopment and implementation of a public web portal. The PD(s)/PI(s)
should devote at least 3 calendar months to the Hub. Key personnel should have
expertise in web programming, database design and management, and
bioinformatics. Expert biological curation and annotation will also be
required. NIDDK and NICHD would like to encourage all qualified applicants
regardless of prior association with NURSA to apply to this FOA. The
information systems, consulting, and database archiving tasks required to
design and execute NURSA are highly technical, and require extensive
experience, expertise, and long-term commitment. It is expected that applicants
will have the technical capability and management skills to independently carry
out this ambitious agenda. PD(s)/PI(s) for NURSA Data Source Projects (NDSP)
should be established, independently funded investigators. The projects should
represent new directions or ideas. Instructions for application along with
topic areas will be posted on the Hub web portal coincident with initiation of
funding. NDSPs may request support for post-doctoral/graduate student effort,
supplies and travel. No equipment may be requested. All NDSP recipients must
agree to follow NURSA policies on data sharing.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed.

Section
IV. Application and Submission Information

1. Address to Request Application Package

Applicants are required to prepare applications according to
the current PHS 398 application forms in accordance with the PHS 398
Application Guide.

2. Content and
Form of Application Submission

It is critical that applicants follow the instructions in
the PHS398
Application Guide, except where instructed in this funding opportunity
announcement to do otherwise. Conformance to the requirements in the
Application Guide is required and strictly enforced. Applications that are out
of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

Applications must be prepared using the PHS 398 research
grant application forms and instructions for preparing a research grant
application. Submit a signed, typewritten original of the application,
including the checklist, and three signed photocopies in one package to:

All page limitations described in the PHS398 Application
Guide and must be followed, with the following requirement:

Research Strategy section is limited to 12 pages.

Consortium Plan

Applicants should provide a plan for how the Hub will serve
to integrate NDSPs, and other projects, to constitute the NURSA Consortium.
Policy and procedures regarding consortia are defined by the NIH Grants Policy
Statement (http://grants.nih.gov/grants/policy/nihgps_2010/nih/gps_ch15.htm).
Applicants should address this policy in defining how NURSA will constitute a
consortium. The NURSA consortium will include investigators from the Hub, the
NDSPs, and may also include collaborations with other NIH funded investigators.
Since the NDSPs will be charged with advancing the scientific and technical
agenda of NURSA funds should be set aside for as many as 6-8 such projects at
up to $150,000 TC per year for 2-5 years beginning in the first year of
funding. The Consortium Hub budget for Resources and the web portal will be
limited to $600,000 TC for each of 5 years. The NDSPs will be funded as
subcontracts from the Hub. Investigators may apply for only 1 NDSP at a time.
NDSP investigators will be members of the SC for the period of time they are
supported by NURSA, though affiliated membership may be offered subsequent to the
end of the project period. The Hub should also budget accordingly for the
annual investigator's retreat including EEC participation.

Research Plan

All instructions in the PHS398 Application Guide must be
followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies; GWAS) as provided in the PHS398
Application Guide, with the following modification:

All applications, from the Hub to the NDSPs should address a Data
Sharing Plan, with the NDSPs agreeing to the relevant NURSA policies on data
sharing.

Appendix

Do not use the Appendix to circumvent page limits. Follow
all instructions for the Appendix (please note all format requirements) as
described in the PHS398 Application Guide, with the following modification:

A draft template for the NURSA Data Source Projects (NDSPs)
applications should be provided.

Applications must be received on or before the due dates in Part I. Overview Information. If an
application is received after that date, it will not be reviewed.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section
V. Application Review Information

1. Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

For this particular announcement, note the following:

The NURSA Hub combines a discovery-based and
hypothesis-generating/testing approach to data accrual and analysis together
with a service role. The research role is therefore different from what might
be expected in a standard R01 application and overall impact may involve
consideration of the role that the Hub plays in integration of emerging and
archived information and its presentation to the broader community. Although
the NDSP program should be discussed, the topics for these projects will await
consultation with leading experts in the field as well as with NIH staff.

Overall Impact - Overall

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of
the following review criteria and additional review criteria (as applicable for
the project proposed).

Scored Review Criteria - Overall

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(S), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented?
If the project is in the early stages of development, will the strategy
establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria - Overall

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Have the applicants provided a plan for solicitation
and review of NDSPs and the integration of successful applicants into the NURSA
consortium?

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of
minorities and members of both genders, as well as the inclusion of children. For
additional information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations - Overall

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NIDDK, in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall
impact/priority score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center and will
compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications
will receive a second level of review by the appropriate national Advisory Council or Board.. The following will be considered in making funding
decisions:

Scientific and technical merit of the proposed project as determined
by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH
Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.]

The administrative and funding instrument used for this
program will be the cooperative agreement, an "assistance" mechanism
(rather than an "acquisition" mechanism), in which substantial NIH
programmatic involvement with the awardees is anticipated during the
performance of the activities. Under the cooperative agreement, the NIH purpose
is to support and stimulate the recipients' activities by involvement in and
otherwise working jointly with the award recipients in a partnership role; it
is not to assume direction, prime responsibility, or a dominant role in the
activities. Consistent with this concept, the dominant role and prime
responsibility resides with the awardees for the project as a whole, although
specific tasks and activities will be shared among the awardees and the NIH as
defined below

Awardee Rights and Responsibilities

Awardees have primary responsibilities for the project as a
whole, including research design, final data analysis and interpretation and
preparation of publications, facilitating outreach to the broader nuclear
receptor research community, and collaboration with other awardees (including
those of the NDSPs); and affiliated members; with assistance from the NIDDK and
NICHD Project Scientists.

The tasks or activities in which awardees have primary
substantial responsibilities include the further development of NURSA and the
web portal (http://www.nursa.org),
management of the NURSA consortium, and scheduling of regular Steering
Committee meetings, including agendas and logistics.

Awardees retain custody and have primary rights to the data
developed under these awards, subject to Government rights of access consistent
with current HHS, PHS and NIH policies. It will be the primary responsibility
of the awardees to rapidly transfer data to the Hub upon verification of the
data.

Since the collection and storage of publicly available data
is expected to be persistent beyond the project period for this announcement,
the development and management of this data repository is a stewardship that
shall be subject to transfer at the end of the project period. Therefore, it
is imperative that the database and core functions of the data repository be
independent of physical location and that the software used is publicly
available.

The Hub must include technology transfer and sharing plans
for both data and unique research resources that are generated by the projects
in concordance with NIH policies on the sharing of data and resources. The
policies should be prominently displayed on the web portal. Is is expected
that resources developed by NURSA members will be made available to the broader
scientific community, after a short propriety period, at no charge other than
the cost of reproduction and distribution. The grant application must also
include a statement indicating the applicant’s willingness to abide by the
Cooperative Agreement Terms and Conditions of the Award.

NIH
Staff Responsibilities:

The NIDDK Project Scientist will serve as the contact point
for all facets of the scientific interaction with the awardee (s). As required
for the coordination of activities and to expedite progress, NIDDK may
designate additional NIDDK staff to provide advice to the awardee on specific
scientific and/or analytic issues. Such staff may include another Project
Scientist(s) or Analyst, who will provide direct technical assistance to the
awardees to optimize the conduct and/or analysis of the study; or who may
assist in the coordination of activities across multiple sites.

The NIDDK Project Scientist will participate in the Steering
Committee that oversees consortium activities and represent the interests of
other co-sponsoring NIH Institutes. The NIDDK Project Scientist or designee
will be a full participant and voting member of the Steering Committee and, if
applicable, subcommittees. NICHD may appoint an additional Project Scientist,
and together with the NIDDK Project Scientist will serve as resources to NURSA investigators
with respect to other ongoing NIH activities that may be relevant to NURSA
activities.

The NIDDK and NICHD Project Scientists will have substantial
involvement in assisting in the design and coordination of research activities
for awardees as elaborated below:

The NIDDK and NICHD Project Scientists or designees may
coordinate activities among awardees by assisting in the design, development,
and coordination of a common research or clinical protocol and statistical
evaluations of data; in the preparation of questionnaires and other data
recording forms; and in the publication of results and in reviewing procedures
for assessing data quality and study performance monitoring.

The NIDDK and NICHD Project Scientists or designees may be
co-authors on study publications. In general, to warrant co-authorship, Project
Scientists must have contributed to the following areas: (a) design of the
concepts or experiments being tested; (b) performance of significant portions
of the activity; (c) participate in analysis and interpretation of study
results and (d) preparation and authorship of pertinent manuscripts.

In addition, a separate NIDDK Program Official identified in
the Notice of Award will be responsible for the normal stewardship and
monitoring of the award including review and approval of all progress reports
and all budgetary decisions. Additional responsibilities include interacting
with the principal investigator(s) on a regular basis to monitor study
progress. Monitoring may include: regular communications with the principal
investigator and staff, periodic site visits, observation of field data collection
and management techniques, quality control, fiscal review, and other relevant
matters; as well as attendance at Steering Committee and related meetings. The
NIDDK Program Official will review and approve protocols prior to
implementation to insure they are within the scope of peer review. The NIDDK
will not permit further expenditures of NIDDK funds for a study after
requesting closure except as specifically approved by the NIDDK. The NIDDK
Program Official will make recommendations for continued funding based on: a)
overall study progress, including sufficient patient and/or data accrual; b)
cooperation in carrying out the research (e.g., attendance at Steering
Committee meetings, implementation of group decisions, compliance with the
terms of award and reporting requirements); and/or c) maintenance of a high
quality of research, which will allow pooling of data and comparisons across
multiple cooperative agreement awards for common data elements.

NIDDK Program and Project Staff, as well as External Evaluation
Committee (EEC) members will be responsible for generating the topics for NURSA
Data Source Projects (NDSP) solicitations and for assuring appropriate peer
review. NIH staff will employ external experts as part of this process through
the External Evaluation Committee (EEC) which will assist in yearly assessment
of progress in meeting milestones. The EEC will also assist with identification
of topics for the NDSPs and in their review. The EEC will be advisory to both
NIH staff and the NURSA Consortium. The NURSA EEC will meet annually to review
interim progress and provide an annual report and recommendations to NIH and to
the Steering Committee on NURSA activities.

Collaborative
Responsibilities:

After an award has been made the awardee will constitute an
investigator's meeting at which a series of milestones will be developed along
with timelines for their completion. A chair of the Steering Committee will be
identified by NIH Staff in consultation with the awardees. In addition, an
External Evaluation Committee will be constituted to meet periodically with the
Awardees and NIH Staff to help evaluate progress against agreed upon
milestones. The Principal Investigators of NURSA must indicate a commitment to
be responsive to recommendations provided by the EEC. The NURSA Steering
Committee will be responsible for organizing and providing minutes of these
meetings. Members of the EEC will be nominated by the NURSA Steering Committee,
selected and invited by the NIH. A chairman will be chosen from among the EEC
membership, who will be accomplished senior scientists from academia and
industry with backgrounds in the mission of NIDDK and the other co-sponsoring
ICs, and technologies associated with web portal development and function,
software use and development, and concepts of large scale data handling and
analysis. If voting is necessary for an action item, members of the EEC and the
EEC chair hold one vote each. The Steering Committee will discuss
implementation of EEC recommendations, and provide a timeline and action plan
for making changes. The action plan will be reported to the EEC.

At the outset at least two Steering Committee meetings will
be held as in person meetings, jointly organized by the Awardees and the NIH
staff. Other Steering Committee meetings will be held as teleconferences on a
schedule defined by common agreement. The EEC will be in attendance at one such
meeting. One of these meetings will be a broad investigator's retreat with all
PIs and designees present at which scientific progress and opportunities will
be presented and discussed. At other Steering Committee meetings. PIs will
focus on strategic issues including development and review of annual milestones
and timelines. The Steering Committee will be responsible for setting policy
for the consortium, including final policies regarding access to the resources
of the Hub. This will be done in consultation with NIH staff. The awardees in
conjunction with NIH staff will also hold or participate in pertinent workshops
designed to further the outreach and relevance of NURSA.

Dispute
Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to arbitration. A dispute resolution panel will be composed
of three members: a designee of the Steering Committee chosen without NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two; in the case of individual disagreement,
the first member may be chosen by the individual awardee. This special dispute
resolution procedure does not alter the awardee's right to appeal an adverse
action that is otherwise appealable in accordance with PHS regulation 42 CFR
Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH
Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.